In order to better understand how schizophrenia risk genetics operate at the cognitive and neural systems level, our recent work under this project has focused on understanding the biological correlates of both polygenic illness risk and gene-by-environment interactions. Ongoing studies in these areas permit better understanding of heritable, trait-related abnormalities in schizophrenia, of the underlying molecular biology responsible for such abnormalities, and of strategies for resolving some of the illness heterogeneity that makes biological research so challenging. Schizophrenia is highly heritable, but its genetic architecture is exceptionally complex. Recent gains in delineating a host of diverse genetic markers that each show small statistical illness association effects in very large cohorts present major challenges and opportunities to understanding molecular pathways to system-level dysfunction in schizophrenia. By generating metrics of cumulative schizophrenia risk burden that combine information from schizophrenia risk polymorphisms across the genome, we have been able to test important hypotheses about illness-linked neuroimaging phenotypes. For instance, following a series of MRI experiments in individuals with schizophrenia in which we have established that hippocampal activity measured during memory encoding may be abnormal in patients and also affected in their relatives, we have shown in collaborative work that cumulative, polygenic risk burden for schizophrenia predicts variability in this measurement in healthy individuals (Chen et al, 2018). We have also shown effects of polygenic risk for late-onset Alzheimers disease on this same measure of hippocampal engagement (Xiao et al, 2017), highlighting the complex molecular underpinnings of these neuroimaging signals. This and similar experimentation incorporating positron emission tomographic measurements ongoing in the Branch provide important validation of target neurophysiological phenotypes that may arise from etiological genetic variation. In conjunction with genetic factors underlying risk for schizophrenia, environmental influences have been identified as illness risk factors in epidemiological and twin studies, and delineating gene-environment interactions is likely crucial to better understanding the causes of schizophrenia. Recent research has highlighted two environmental variables that show association with schizophrenia: urbanicity and early life complications. For instance, we have demonstrated that whether an individual was raised in an urban environment significantly modifies effects of dopamine-related genes on how the prefrontal cortex responds to working memory demands (Reed et al, 2018). We have further replicated this finding in two additional datasets and posit that urban upbringing may alter brain function in a way that meaningfully intersects with dopaminergic neurogenetic mechanisms. Other work suggests that the predictive strength of most strongly associated loci from the recent schizophrenia genome-wide association study is greatly amplified when there is a history of clinically significant obstetrical complications (Ursini et al, 2018). These data suggest that traditional univariate approaches must be buttressed by gene-by-environment experimentation to more fully elaborate genetic risk architecture in schizophrenia.